1. Technical Field
This invention relates to methods for non-invasively determining biological tissue oxygenation in general, and to non-invasive methods utilizing near-infrared spectroscopy (NIRS) techniques in particular.
2. Background Information
The molecule that carries the oxygen in the blood is hemoglobin. Oxygenated hemoglobin is called oxyhemoglobin (HbO2) and deoxygenated hemoglobin is deoxyhemoglobin (Hb). Total hemoglobin is the summation of the two states of hemoglobin (Total Hb=HbO2+Hb), and is proportional to relative blood volume changes, provided that the hematocrit or hemoglobin concentration of the blood is unchanged. The mammalian cardiovascular system consists of a blood pumping mechanism (the heart), a blood transportation system (blood vessels), and a blood oxygenation system (the lungs). Blood oxygenated by the lungs passes through the heart and is pumped into the arterial vascular system. Under normal conditions, oxygenated arterial blood consists predominately of HbO2. Large arterial blood vessels branch off into smaller branches called arterioles, which profuse throughout biological tissue. The arterioles branch off into capillaries, the smallest blood vessels. In the capillaries, oxygen carried by hemoglobin is transported to the cells in the tissue, resulting in the release of oxygen molecules (HbO2xe2x86x92Hb). Under normal conditions, only a fraction of the HbO2 molecules give up oxygen to the tissue, depending on the cellular metabolic need. The capillaries then combine together into venuoles, the beginning of the venous circulatory system. Venuoles then combine into larger blood vessels called veins. The veins further combine and return to the heart, and then venous blood is pumped to the lungs. In the lungs, deoxygenated hemoglobin Hb collects oxygen becoming HbO2 again and the circulatory process is repeated.
Oxygen saturation is defined as:                                           O            2                    ⁢                      xe2x80x83                    ⁢          saturation          ⁢                      xe2x80x83                    ⁢          %                =                                            HbO              2                                      (                                                HbO                  2                                +                Hb                            )                                xc3x97          100          ⁢          %                                    (Eqn.  1)            
In the arterial circulatory system under normal conditions, there is a high proportion of HbO2 to Hb, resulting in an arterial oxygen saturation (defined as SaO2 %) of 95-100%. After delivery of oxygen to tissue via the capillaries, the proportion of HbO2 to Hb decreases. Therefore, the measured oxygen saturation of venous blood (defined as SvO2 %) is lower and may be about 70%.
One spectrophotometric method, called pulse oximetry, determines arterial oxygen saturation (SaO2) of peripheral tissue (i.e. finger, ear, nose) by monitoring pulsatile optical attenuation changes of detected light induced by pulsatile arterial blood volume changes in the arteriolar vascular system. The method of pulse oximetry requires pulsatile blood volume changes in order to make a measurement. Since venous blood is not pulsatile, pulse oximetry cannot provide any information about venous blood.
Near-infrared spectroscopy (NIRS) is an optical spectrophotometric method of continually monitoring tissue oxygenation that does not require pulsatile blood volume to calculate parameters of clinical value. The NIRS method is based on the principle that light in the near-infrared range (700 to 1,000 nm) can pass easily through skin, bone and other tissues where it encounters hemoglobin located mainly within micro-circulation passages; e.g., capillaries, arterioles, and venuoles. Hemoglobin exposed to light in the near infra-red range has specific absorption spectra that varies depending on its oxidation state; i.e., oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb) each act as a distinct chromophore. By using light sources that transmit near-infrared light at specific different wavelengths, and measuring changes in transmitted or reflected light attenuation, concentration changes of the oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb) can be monitored. The ability to continually monitor cerebral oxygenation levels is particularly valuable for those patients subject to a condition in which oxygenation levels in the brain may be compromised, leading to brain damage or death.
The apparatus used in NIRS analysis typically includes a plurality of light sources, one or more light detectors for detecting reflected or transmitted light, and a processor for processing signals that represent the light emanating from the light source and the light detected by the light detector. Light sources such as light emitting diodes (LEDs) or laser diodes that produce light emissions in the wavelength range of 700-1000 nm at an intensity below that which would damage the biological tissue being examined are typically used. A photodiode or other light source detector is used to detect light reflected from or passed through the tissue being examined. The processor takes the signals from the light sources and the light detector and analyzes those signals in terms of their intensity and wave properties.
It is known that relative changes of the concentrations of HbO2 and Hb can be evaluated using apparatus similar to that described above, including a processor programmed to utilize a variant of the Beer-Lambert Law, which accounts for optical attenuation in a highly scattering medium like biological tissue. The modified Beer-Lambert Law can be expressed as:
Axcex=xe2x88x92log(I/Io)xcex=xcex1xcex*C*d*Bxcex+G xe2x80x83xe2x80x83(Eqn.2) 
wherein xe2x80x9cAxcexxe2x80x9d represents the optical attenuation in tissue at a particular wavelength xcex (units: optical density or OD); xe2x80x9cIoxe2x80x9d represents the incident light intensity (units: W/cm2); xe2x80x9cIxe2x80x9d represents the detected light intensity; xe2x80x9cxcex1xcexxe2x80x9d represents the wavelength dependent absorption coefficient of the chromophore (units: OD * cmxe2x88x921 * xcexcMxe2x88x921); xe2x80x9cCxe2x80x9d represents the concentration of chromophore (units: xcexcM); xe2x80x9cdxe2x80x9d represents the light source to detector (optode) separation distance (units: cm); xe2x80x9cBxcexxe2x80x9d represents the wavelength dependent light scattering differential pathlength factor (unitless); and xe2x80x9cGxe2x80x9d represents light attenuation due to scattering within tissue (units: OD).
Absolute measurement of chromophore concentration (C) is very difficult because G is unknown or difficult to ascertain. However, over a reasonable measuring period of several hours to days, G can be considered to remain constant, thereby allowing for the measurement of relative changes of chromophore from a zero reference baseline. Thus, if time t1 marks the start of an optical measurement (i.e., a base line) and time t2 is an arbitrary point in time after t1, a change in attenuation (xcex94A) between t1 and t2 can be calculated, and variables G and Io will cancel out providing that they remain constant.
The change in chromophore concentration (xcex94C=C(t2)xe2x88x92C(t1)) can be determined from the change in attenuation xcex94A, for example using the following equation derived from the Beer-Lambert Law:
xcex94A=xe2x88x92log(It2/It1)xcex=xcex1xcex*xcex94C*d*Bxcexxe2x80x83xe2x80x83(Eqn.3) 
Presently known NIRS algorithms that are designed to calculate the relative change in concentration of more than one chromophore use a multivariate form of Equation 2 or 3. To distinguish between, and to compute relative changes in, oxyhemoglobin (xcex94HbO2) and deoxyhemoglobin (xcex94Hb), a minimum of two different wavelengths are typically used. The concentration of the HbO2 and Hb within the examined tissue is determined in xcexmoles per liter of tissue (xcexcM).
The above-described NIRS approach to determining oxygen saturation levels is useful, but it is limited in that it only provides information regarding a change in the level of blood oxygen saturation within the tissue. It does not provide a means for determining the total level of blood oxygen saturation within the biological tissue.
At present, information regarding the relative contributions of venous and arterial blood within tissue examined by NIRS is either arbitrarily chosen or is determined by invasive sampling of the blood as a process independent from the NIRS examination. For example, It has been estimated that NIRS examined brain tissue consists of blood comprising from about 60 to 80% venous to about 20 to 40% arterial blood. Blood samples from catheters placed in venous drainage sites such as the internal jugular vein, jugular bulb, or sagittal sinus-have been used to evaluate NIRS measurements. It has been estimated in animal studies that NIRS interrogated tissue consists of a mixed vascular bed with a venous-to-arterial ratio of about 2:1 as determined from multiple linear regression analysis of sagittal sinus oxygen saturation (SSSO2) and carotid artery oxygen saturation (SaO2) in comparison to NIRS measured xcex94Hb and xcex94HbO2. An expression representing the mixed venous/arterial oxygen saturation (SmvO2) in NIRS examined tissue is shown by the equation:
SmvO2=Kv*SvO2+Ka*SaO2 xe2x80x83xe2x80x83(Eqn.4) 
where xe2x80x9cSvO2xe2x80x9d represents venous oxygen saturation; xe2x80x9cSaO2xe2x80x9d represents arterial oxygen saturation; and Kv and Ka are the weighted venous and arterial contributions respectively, with Kv+Ka=1. The parameters Kv and Ka may have constant values, or they may be a function of SvO2 and SaO2. Determined oxygen saturation from the internal jugular vein (SijvO2), jugular bulb (SjbO2), or sagittal sinus (SssO2) can be used to represent SvO2. Therefore, the value of each term in Equation 4 is empirically determined, typically by discretely sampling or continuously monitoring and subsequently evaluating patient arterial and venous blood from tissue that the NIRS sensor is examining, and using regression analysis to determine the relative contributions of venous and arterial blood independent of the NIRS examination.
What is needed, therefore, is a method for non-invasively determining the level of oxygen saturation within biological tissue that can determine the total oxygen saturation level rather than a change in level; a method that provides calibration means to account for light attenuation due to scattering within tissue (G); and a method that can non-invasively distinguish the contribution of oxygen saturation attributable to venous blood and that which is attributable to arterial blood.
It is, therefore, an object of the present invention to provide a method for non-invasively determining the total level of blood oxygen saturation within biological tissue.
It is a further object of the present invention to provide a method that provides calibration means to account for light attenuation due to scattering within tissue, light attenuation due to fixed tissue absorbers, and light attenuation due to variability between light measuring apparatuses.
It is a still further object of the present invention to provide a method that can non-invasively distinguish between the contribution of oxygen saturation attributable to venous blood and that attributable to arterial blood.
According to the present invention, a method and apparatus for non-invasively determining the blood oxygen saturation level within a subject""s tissue is provided that utilizes a near infrared spectrophotometric (NIRS) sensor capable of transmitting a light signal into the tissue of a subject and sensing the light signal once it has passed through the tissue via transmittance or reflectance. The method includes the step of determining attenuation of the light signal as the sum of: (i) attenuation attributable to deoxyhemoglobin; (ii) attenuation attributable to oxyhemoglobin; and (iii) attenuation attributable to light scattering within the subject""s tissue. The present method also makes it possible to account for attenuation attributable to fixed or constant light absorbing biological tissue components, and attenuation attributable to variable characteristics of the sensor. By determining differential attenuation as a function of wavelength, the attenuation attributable to tissue light scattering characteristics, fixed light absorbing components, and measuring apparatus characteristics are mathematically cancelled out or minimized relative to the attenuation attributable to deoxyhemoglobin, and attenuation attributable to oxyhemoglobin.
In order to account for the resulting minimized differential attenuation attributable to tissue light scattering characteristics, fixed light absorbing components, and measuring apparatus characteristics, each of the parameters must be measured or calibrated out. Since direct measurement is difficult, calibration to empirically determined data combined with data developed using the NIRS sensor is performed by using regression techniques. The empirically determined data is collected at or about the same time the data is developed with the NIRS sensor. Once the calibration parameters associated with attenuation attributable to tissue light scattering characteristics, fixed light absorbing components, and measuring apparatus characteristics have been determined, the NIRS sensor can be calibrated.
The calibrated sensor can then be used to accurately and non-invasively determine the total oxygen saturation level in the original subject tissue or other subject tissue. In addition, if the separation distance (xe2x80x9cdxe2x80x9d) between the light source to the light detector is known or is determinable, and if the value of xe2x80x9cBxe2x80x9d, which represents the wavelength dependent light scattering differential pathlength factor, is known, then the total amount of concentrations of deoxyhemoglobin (Hb) and oxyhemoglobin (HbO2) within the examined tissue can be determined using the present method and apparatus.
The calibrated sensor can be used subsequently to calibrate similar sensors without having to invasively produce a blood sample. Hence, the present method and apparatus enables a non-invasive determination of the blood oxygen saturation level within tissue. For example, an operator can create reference values by sensing a light signal or other reference medium using the calibrated sensor. The operator can then calibrate an uncalibrated sensor by sensing the same light signal or reference medium, and subsequently adjusting the uncalibrated sensor into agreement with the calibrated sensor. Hence, once a reference sensor is created, other similar sensors can be calibrated without the need for invasive procedure.
There are, therefore, several advantages provided by the present method and apparatus. Those advantages include: 1) a practical non-invasive method and apparatus for determining oxygen saturation within tissue that can be used to determine the total blood oxygen saturation within tissue as opposed to a change in blood oxygen saturation; 2) a calibration method that accounts for light attenuation due to scattering within tissue (G), fixed tissue absorbers (F), and measuring apparatus variability (N); and 3) a practical non-invasive method and apparatus for determining oxygen saturation within tissue that can distinguish between the contribution of oxygen saturation attributable to venous blood and that saturation attributable to arterial blood.
In an alternative embodiment, aspects of the above-described methodology are combined with pulse oximetry techniques to provide a non-invasive method of distinguishing between blood oxygen saturation within tissue that is attributable to venous blood and that which is attributable to arterial blood. Pulse oximetry is used to determine arterial oxygen saturation, and the arterial oxygen saturation is, in turn, used to determine the venous oxygen saturation.
These and other objects, features, and advantages of the present invention method and apparatus will become apparent in light of the detailed description of the invention provided below and the accompanying drawings. The methodology and apparatus described below constitute a preferred embodiment of the underlying invention and do not, therefore, constitute all aspects of the invention that will or may become apparent by one of skill in the art after consideration of the invention disclosed overall herein.